DE1000386C2 - Process for the production of new quinazoline derivatives - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

PATENT LETTER 1 000 ON REPORTING DAY:

NOTICE THE REGISTRATION AND ISSUE OF EDITORIAL:

ISSUE OF PATENT LETTERING:

kl. 12 ρ 10

INTERNAT. KL. C 07 d

AUGUST 5, 1954

JANUARY 10, 1957 JUNE 27, 1957

agrees with the exposition

1000 38 «(I 8991 IVb / 12 p)

The invention relates to the preparation of new quinazoline derivatives of the structural formula

in which R ₁ , R ₂ and X are hydrogen or a lower alkyl radical, Y is hydrogen, halogen or a lower alkyl radical and Z is an NHR ₃ group, in which R _{8 is} hydrogen or an acyl radical and which is in the 7th or 8th group Position of the quinazoline ring system.

It has been found that substances of this structure, e.g. B. 4,7- and 4,8-diaminochinazoline, a strong diuretic Combine effect with very low toxicity and the well-known, diuretic compounds are superior.

The following are mentioned as new quinazoline derivatives: 4, 7-Diaminochinazoun, 4-Annno-7-acetamidoquinazoline, 4-methylamino-7-amino quinazoline, 4-D1-methylamino-7-amino quinazoline, 4-ethylamino-7-amino quinazoline, 4-isopropylamino-7-amino quinazoline, 4-n-Bu- »5 tylamino-7-aminochinazoline, 4-n-butylamino-7-acetamidoquinazoline, 4, 8-diaminochinazoline, 4, 8-diamino-6-chloroquinazoline, 4,7-diamino-2-methylquinazoMn,

4, 7-diamino-6-methyIchinazoline, 4 ~ amino-7-butyramidoquinazoline.

The inventive method for producing these Quinazoline derivatives consist in the reduction of compounds of the structural formula

R ₃ -NR ₁

35

NO ₂

in which R ₁ , R ₂ , X and Y have the meaning given above and the nitro group is in the 7- or 8-position of the quinazoline ring system, if necessary with subsequent acylation of the reduction product.

The reduction can be carried out with reducing agents, such as. B. tin chloride or with metal powders, e.g. B. iron powder, in an aqueous acidic medium such as aqueous hydrochloric acid.

As mentioned, the reduction product can then if necessary, acylated in a manner known per se. For this purpose, z. B. a mixture of a suitable acid with its anhydride, e.g. B. a mixture process for making new Quinazoline derivatives

Patented for:

Imperial Chemical Industries Limited, London

Claimed priority: Great Britain - August 7, 1953 and July 28, 1954

Alfred Spinks and Edwin Harry Paterson Young, Blackley, Manchester (Great Britain), have been named as inventors

of acetic acid with acetic anhydride, use Find.

The following examples, in which the parts relate to amounts by weight, serve to illustrate the Invention, they are not intended to limit them.

example 1

A mixture of 20 parts of iron powder, 10 parts of concentrated aqueous hydrochloric acid and 500 parts of water is heated with stirring for 15 minutes at 95 ^0th Then, 19 parts of 4-amino-7-nitroquinazoline are added, and the mixture is kept under stirring for 5 hours at 95 ^0th Then it is mixed with sodium carbonate until it has an alkaline reaction against brilliant yellow and filtered hot. The solid residue is washed with 100 parts of hot water. The filtrate is combined with the washing liquids, cooled and nitrated and the solid residue is recrystallized from water. To give 4, 7-Diaminochinazolin as colorless needles melting at 253-254 ^0th

2.6 parts of acetic anhydride are added to a solution of 4 parts of 4, 7-Diaminochinazolin in 26 parts of glacial acetic acid, and the mixture is heated for 10 minutes at ioo °, then cooled to 20 ⁰ and added to 250 parts of water and 100 parts of ice . The mixture is filtered and the filtrate is made alkaline to brilliant yellow by adding concentrated aqueous ammonia. The mixture is filtered and the solid residue is recrystallized from water, 7-acetamido-4-aminochinazoline as a colorless, solid, crystalline

7 »563/293

line mass from melting point 349 to 350 ⁰ (under Zer- The 4-ethylamino-7- used as starting material

setting) receives. nitroquinazoline can be presented by one

Example 2 ²⁰ ^ eüe ^ -Chlor ^ -nitroquinazoline rapidly with stirring

to 80 parts, a 24% solution of ethylamine

A mixture of 5 parts of iron powder, 2 parts of 5 20 ^{0 is} added. Then the mixture is for 15 minutes

concentrated aqueous hydrochloric acid and 200 parts of water kept at 60 to 70 "and then cooled ^{to 20 0,}

is stirred for 15 minutes at 95 to 100 °. Then the mixture is diluted with 200 parts of water

heats. After adding 5 parts of 4-methylamino-7-nitro and filtered. The solid residue is washed with cold water

quinazoline to the mixture, this is washed for a further 6 hours and recrystallized from 70 parts of ethanol,

stirred for a long time at 95 to 100 °. It is then filtered and the 10 is obtained 4-ethylamino-7-nitroquinazoline as a yellow,

Filtrate by adding sodium carbonate against a crystalline, solid mass; Mp. 195 to 197 ⁰ .
Made brilliant yellow alkaline and filtered again. to

the filtrate will be 72 parts 4o ° / ₀ aqueous sodium hydroxide solution Example 5
is added and the mixture is filtered. The firm one

The residue is recrystallized from water, and a mixture of 10 parts of iron powder, 10 parts

receives 7-amino-4-methylaminoquinazoline as pale cream-concentrated aqueous hydrochloric acid and 100 parts of water

colored solid fabric; Melting point 221 °. is heated to 95 to 100 ° with stirring until it does not

The 4-methylamino used as starting material reacts acidic against Congo red. Then will

7-nitroquinazoline can be added 8 parts of 4-isopropylamino ^ 7-nitroquinazoline by adding 20 parts,

4-Chloro-7-nitroquinazoline with stirring over the course of 20 and the mixture is left with stirring for 6 hours

For 30 minutes, 200 parts of a 23 ° / ₀ strength aqueous solution 95 to 100 ° held. Then she is by adding

of methylamine at 45 to 50 °. The sodium carbonate made alkaline against brilliant yellow

Mixture is then nitrated for an additional 15 minutes at 45 bis and. The solid residue is 20 parts

50 ⁰ stirred, cooled and filtered. The solid residue is washed with hot water, which is mixed with the washing liquid

is washed twice with 50 parts of water and 25 keiten of combined filtrate is washed with 25 parts of 40% ^r

then recrystallized from water. 4-Methyl-sodium hydroxide solution is obtained, and the solution thus obtained is made alkaline

amino-7-nitroquinazoline in the form of yellow needles; Mp. 245 mixture is extracted with 210 parts of ether. the

up to 246 °. Ether extract is dried, then with dry

Example 3 Saturated and nitrated hydrogen chloride gas. The firm one

30 residue is dissolved in 24 parts of methanol and washed through

A mixture of 10 parts of iron powder, 5 parts of addition of 135 parts of ethyl acetate precipitated. You get

concentrated aqueous hydrochloric acid and 100 parts of water 7-amino-4-isopropylaminozoline dihydrochloride as

becomes colorless, solid, crystalline mass with stirring for 15 minutes at 95 to 100 °; Mp. 239 to 240 ⁰ .

heats. Then 6 parts of 4-dimethylamino-7-nitro- The 4-isopropylamino used as starting material

quinazoline added and the mixture is 6 hours 35 7-nitroquinazoline can be prepared by

kept at 95 to 100 ° for a long time with stirring. Then filtered 20 parts of 4-chloro-7-nitroquinazoline to 35 parts of iso-

one, the filtrate is added by adding sodium carbonate propylamine at 20 ⁰ with stirring. One lets

to a p _H of 8, a cooking and filtered hot. Let the mixture stand for 1 hour, then dilute with 500 parts

The filtrate is cooled, left to stand and then again len cold water and filtered. The solid residue

filtered. The solid residue is recrystallized from water and washed with cold water from 200 parts

lized, whereby 7-amino-4-dimethylaminoquinazoline 5o ° / ₀ strength aqueous methanol is recrystallized. Man

as colorless needles of melting point 89 to 91 ^0th receives 4-isopropylamino-7-nitroquinazoline as a yellow, solid,

The 4-dimethylamino-crystalline mass used as starting material; M.p. 161 to 163 °.

7-nitroquinazoline can be prepared by adding _R. ,

20 parts of 4-chloro-7-nitroquinoline with stirring to 200 parts 45 Example ο

len a 24 ° / _o aqueous solution of dimethylamine A mixture of 5 parts of concentrated aqueous

at 45 to 50 ⁰ clogs. The mixture is then 10 minutes hydrochloric acid, 10 parts iron powder and 250 parts water

^{heated to 70 0} for a long time and then allowed to cool to 20 °, is stirred for 30 minutes at 95 to 100 °

whereupon they are left to stand for 16 hours. Then filtered heats. Then over the course of an hour at 95 bis

one, the solid residue washes with cold water 50 ioo ° 10 parts of 4-n-butylamino-7-nitroquinazoline to-

and recrystallized it from 150 parts of ethanol. Set and mix for an additional 6 hours

receives 4-dimethylamino-7-nitroquinazoline as a yellow, kept at 95 to 100 ° with stirring and then hot

Crystals with a melting point of 171 to 173 ⁰ . filtered. The hot filtrate is adjusted by adding sodium carbonate to a p _H of 8, and filtered.

Example 4 55 This filtrate is mixed with 20 parts 4o ° / ₀ sodium hydroxide solution

made alkaline and the mixture thus obtained with

A mixture of 10 parts of iron powder, 5 parts of 280 parts of ether extracted at 30 ^0th The ether extract of concentrated aqueous hydrochloric acid and 100 parts of water is dried, concentrated to about 150 parts, cooled and filtered at 95 ° to 100 ° for 10 minutes with stirring. 7-Amino-4-n-butylaminoquine is obtained heated. Then 5.3 parts of 4-ethylamino-7-nitro-60 azoline as a colorless, solid, crystalline mass; Mp. 150 to 152 ⁰ . quinazoline is added and the mixture is kept under stirring. The 4-n-butylamino-used as starting material is kept at 95 ° to 100 ° for 5 hours. The mixture of 7-nitroquinazoline can be prepared by making it all-yellow alkaline by adding sodium carbonate against brilliant-20 parts of 4-chloro-7-nitroquinazoline with stirring and filtering. The solid residue is gradually added to 38 parts of n-butylamine at 20 °. This is washed with 20 parts of hot water. The 65 mixture is then kept at 80 ° for 15 minutes, the filtrate combined with the washing liquids is cooled, poured into 2000 parts of cold water and filtered, and the solid residue is extracted from water. The solid residue is washed with cold water, recrystallized. 7-Amino-4-äthylamino- is added to a mixture of 950 parts of water and 45 parts of quinazoline in a form containing water of crystallization as colorless concentrated aqueous hydrochloric acid and filtered. Needles from melting point 99 to 100 °. 70 The filtrate is made with concentrated aqueous ammonia

made alkaline to give 4-n-butylamino-7-nitroquinazoline; Mp. 142 to 144 ⁰ .

A mixture of 1.1 parts of 7-amino-4-n-butylaminoquinazoline, 10.5 parts of glacial acetic acid and 0.65 parts of acetic anhydride is heated to the boil. Then allowed to cool the mixture to 20 ^0, it is poured into 100 parts of cold water, it makes with concentrated aqueous ammonia, alkaline and filtered. The solid residue is washed with cold water and recrystallized from aqueous ethanol. 7-Acetamido-4-n-butylaminoquinazoline is obtained; Mp. 303 to 304 ⁰ (with decomposition).

Example 7

A mixture of 10 parts of iron powder, 5 parts of concentrated aqueous hydrochloric acid and 100 parts of water is heated to 95 to 100 ° with stirring until it no longer reacts acidic to Congo red. Then 5 parts of 4-amino-8-nitroquinazoline are added, the mixture is kept at 95 to 100 ° for 6 hours with stirring and then filtered. The filtrate is made alkaline by adding concentrated aqueous ammonia, filtered and the solid residue is extracted with 100 parts of ethanol. The ethanol extract is concentrated to about 20 parts, cooled and filtered. The solid residue is recrystallized from water; 4,8-diaminochinazoline is obtained as a colorless, solid, crystalline mass; Mp. 210 to 212 ⁰ .

The 4-amino-8-nitroquinazoline used as starting material can be prepared by gradually adding 11.3 parts of 4-chloro-8-nitroquinazoline over a period of 10 minutes with stirring to a mixture of 50 parts of phenol and 25 parts of ammonium carbonate at 90 to 95 ⁰ admits. The mixture is kept at 90 ° to 95 ° for 1 hour with stirring, the alkaline reaction against brilliant yellow being maintained by adding ammonium carbonate, if necessary. Then, the mixture is cooled and poured into 1000 parts of cold water, whereupon 4o / ₀ ° is added aqueous sodium hydroxide until the mixture reacts strongly alkaline. The mixture is filtered, the solid residue is washed with cold water, dried and put it under stirring over 10 minutes to 100 parts of ammonium acetate at 140 to 150 ⁰ to. The mixture is kept at 140 to 150 ^° for 30 minutes, cooled, diluted with 150 parts of water and filtered. The solid residue is washed out with cold water and added to a mixture of 5 parts of concentrated aqueous hydrochloric acid and 100 parts of water at 95 °, whereupon it is filtered. The filtrate is made alkaline with concentrated aqueous ammonia and filtered again, and the solid residue is washed with cold water and recrystallized from water. 4-Amino-8-nitroquinazoline is obtained as a yellow, solid, crystalline mass; Mp. 284 to 286 ° (with decomposition).

Example 8

10 parts of tin chloride become one with stirring Suspension of 2 parts of 4-amino-6-chloro-8-nitroquinazoline in 60 parts of concentrated aqueous hydrochloric acid at 20 ° added. Then the mixture is refluxed for 3 minutes, cooled by adding 40% strength aqueous sodium hydroxide solution made strongly alkaline and then filtered. The solid residue is twice with 50 parts each Washed cold water, then added to 40 parts of ethanol and filtered. The filtrate is evaporated; 6-chloro-4,8-diaminochinazoline is obtained as crystalline solid mass. Mp. 258-259 °.

The 4-amino-6-chloro-8-nitroquinazoline used as starting material can be made as follows:

A mixture of 10 parts of 3-nitro-5-chloranthranilic acid and 22.5 parts of formamide is heated ^{to 155.degree. C. for 12 hours.} The mixture is cooled and extracted twice with 200 parts each of an aqueous solution of bicarbonate. The solid residue is washed with cold water, dried and recrystallized from nitrobenzene, 6-chloro-4-oxy-8-nitroquinazoline being obtained as a yellow, crystalline, solid mass with a melting point of 245 ° to 246 °.

A mixture of 3.1 parts of δ-chloro ^ -oxy-S-nitroquinazoline, 3 parts of phosphorus pentachloride and 42 parts of phosphorus oxychloride is refluxed for 1 hour. The solution is then cooled, 80 parts of petroleum ether (40 to 60 °) are added, and the mixture is filtered. The solid residue is washed with petroleum ether (bp 40 ° to 60 °), and 4,6-dichloro-8-nitroquinazoline is obtained; Mp. 152 to 153 ⁰ .

25.2 parts of 4, o-dichloro-S-nitroquinazoline are im Walk 30 minutes to a mixture with stirring

ao of 200 parts of phenol and 100 parts of ammonium carbonate at 90 to 95 ⁰ added. The mixture is held at 90 to 95 ^° for a further hour, then cooled and poured into 2000 parts of cold water. The mixture is made alkaline with 4o ° / ₀ aqueous sodium hydroxide solution against Claytongelb and nitrided. The solid residue is washed with cold water and dried, and the thus obtained 6-chloro-8-nitro-4-phenoxyquinazoline (mp. 300-302 ⁰⁾ is added to 200 parts of ammonium acetate at 140 to 150 ⁰ in the course of 5 minutes .

The mixture is kept at 140 to 150 ^° for 1 hour, then cooled and poured into 500 parts of cold water and filtered.

The solid residue is washed with cold water, then added to a mixture of 24 parts of concentrated aqueous hydrochloric acid and 280 parts of water at 95 to 100 ° and filtered. The filtrate is made alkaline with concentrated aqueous ammonia to give 4-amino-6-chloro-8-nitroquinazoline; Fp. 284-285 ^0th

Claims (2)

PATENT CLAIMS: i. Process for the production of new quinazoline derivatives the structural formula R ₂ -NR ₁ in which R ₁ , R ₂ and X are hydrogen or a lower alkyl radical, Y is hydrogen, halogen or a lower alkyl radical and Z is an NHR ₃ group, in which R _{3 is} hydrogen or an acyl radical and which is in the 7th or 8th group Position of the quinazoline ring system, characterized in that compounds of the structural formula ND, in which R ₁ , R ₂ , X and Y have the meanings given above and the nitro group is in 7- or 7 8 8-position of the quinazoline ring system is located in the medium, especially in aqueous hydrochloric acid, as reduced and the reduction product, if necessary, reducing agent. then acylated. 2. The method according to claim i, characterized by documents considered: the use of tin chloride or a metal 5 C. Weygand, organic-chemical experiment powder, especially iron powder, in aqueous, acidic art, 1948, p. 351, item 2. © 609 740/408 12.56 (709 »3/293 6.57)